We propose to determine the effects of endogenous and exogenous female sex hormones on recovery of perhaps the most critical motor function impaired by cervical spinal cord injury (SCI): breathing. Although endogenous estrogens and progestins promote recovery following traumatic brain injury, their impact on motor recovery after SCI is unknown. Fluctuations in these hormones during the estrous cycle in female rodents suggest that potential "neuroprotective" effects may depend on the time of the injury. The first hypothesis guiding this proposal is that the estrous cycle stage and corresponding levels of progesterone (a progestin) and 17beta-estradiol (an estrogen) at the time of SCI will correlate with motor recovery (Aim 1). Administration of exogenous progesterone and 17beta-estradiol has been shown to improve locomotor recovery after SCI. However, these hormones are also powerful respiratory stimulants. Data collected by the P.I. and others indicates that respiratory stimulation after SCI strengthens existing spinal synaptic inputs to phrenic motoneurons. Thus, sex hormone therapy targeting respiratory insufficiency may combine generalized neuroprotective effects with effects specific to the phrenic motor system. Accordingly, our second hypothesis is that administration of exogenous progesterone and 17beta-estradiol after cervical SCI will improve respiratory motor recovery (Aim 2). These hypotheses will be tested using behavioral, neurophysiological, and immunoassay techniques in rats. Ventilation will be assessed in unanesthetized rats via barometric plethysmography. Phrenic output will be quantified under anesthesia, and plasma hormone levels will be measured with ELISA. These data will help establish 1) if endogenous gender hormones can influence preclinical SCI research, and 2) if progesterone and 17p-estradiol hormone therapy is an effective means of promoting persistent respiratory recovery following cervical SCI.